Nu-arylcarbamyl-glucosamines



United States Patent Office 3,158,598 Patented Nov. 24, 1964 3,158,598 N-ARYLCARBAMYL-GLUCGSA Charles Morel, Arlesheim, Basel-Land, Switzerland, assignor to Geigy Chemical @orporation, Ardsley, N.Y., a corporation of Delaware No Drawing. Filed Feb. 25, 1-963, Ser. No. 26%,877 Claims priority, application Switzerland, June 21, 1960,

4 Claims. Renate-211.5

This application is a continuation-in-part of my copending application Serial No. 118,242, filed June 20, 1961, now abandoned.

p The present invention relates to new derivatives of glucosamine and more particularly to new N-arylcarbamylglucosamines which have valuable pharmacological properties.

The novel compounds are characterized by a tetrahydroimidazole moiety fused with a D-glucopyrano moiety.

The nitrogen atom in B-position of the tetrahydroimidazole moiety is substituted by a phenyl group which bears in turn substituents as defined below; the. carbon atom in 2-position of the tetrahydroimidazole moiety is substituted with either oxygen or sulfur.

Hitherto, phenylureas substituted with l-desoxy sugar alcohol radicals such as the sorbityl radical and cyclic urethanes thereof have been used as herbicidal compositions, as insecticides, solvents, agents for Supplying rewetting properties to wet strength resins in the paper industry, and as depressants of the surface tension of water, foam, stabilizers, and detergents. The cyclic sorbityl-urethanes have also been recommended in agriculture on account of their anti-bacterial systemic activity and fungicidal activity coupled with their lack of phytotoxieity.

It has now been discovered that, surprisingly, the abovementioned compounds, which are distinguished by the above-mentioned moiety of the formula jej OH H N l, I Q? 1 from the known cycliccompounds which possess sorbitylurethane ring structures as follows:

III-CH3 I o I o H HN (I) in which R represents a member selected from the group consisting of halogen, lower alkyl, lower alkoxy, trifluoromethyl and nitrogroups,

R represents a member selected from the group consisting of hydrogen, halogen, lower alkyland lower al-koxy groups, and

X represents a member selected from the group consisting of oxygen and sulfur,

possess antiphlogistic, anti'pyretic' and serotonin-antagonistic activity and are therapeutically useful for the treatment of inflammations of the respiratory system on oral or parenteral administration.

The compounds of Formula I are obtained by (a) Reacting aor ,8-1,3,4,6-tetra-acetyl-D-pyranoglucosamine with a compound of the general formula R2 (II) wherein R R and X have the meanings given above,

(1)), Converting'the, reaction product of the formula CHzO--AG o III, 0A0 AeO OAe H in a lower alkanol, into the corresponding compound of the formula R: (IV) wherein R R and X have the meanings given above, and

(0) subjecting the compounds of Formula IV, prefer- I ably in the reaction mixture resulting from step (b) above, to ring closing conditions, for example, heating in water, in an aqueous-organic acid such as, e.g., 20% acetic acid or in an organic acid such as, e.g., glacial acetic acid or formic acid, or treating with a dilute mineral acid in the cold or,,also, while heating preferably to about to C.

In the compounds of the Formula I, R is, for example, chlorine, fluorine, bromine, the nitro, trifluoromethyl,

methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-amyl, isoamyl, diethylmethyl, tertiary amyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-amyloxy or isoamyloxy group. R is, for example, hydrogen or one of the substituents given for R with the exception of the nitro group and the tllflllOIOlTlGthYl group.

Of particular value are compounds wherein R is chlorine, the methyl group or the methoxy group, R is hydrogen, chlorine, or the methyl group, and X is sulfur.

The following examples further illustrate the preparation of compounds of Formula I as well as of compounds of Formula IV. Parts are given as parts by weight; their relationship. to parts by volume is at that of grams to cubic centimetres The temperatures are in degrees centigrade.

EXAMPLE 1 (a) 3.6 parts of 13-1,3,4,6-tetra-acetyl-D-pyranogluco- 3 samine' (Berichte 64B, 975 (1931)) and 2.1 parts of 3,4- dichlorophenyl isocyanate in 70 parts by volume of anhydrous benzene are boiled under reflux for 2 hours while excluding moisture. After cooling, the 6-l,3,4,6-tetraacetyl-N- 3 ,4-dichlorophenyl-carbamoyl )'-D-pyranoglucosamine is filtered off, washed with benzene and recrystallized from alcohol. M.P. l90-19l, [011 +368", c.=l.02 in dimethyl formamide.

(b) 5 parts of the above product are dissolved in 50 parts by volume of anhydrous methanol and, at 0, 100 parts of ammonia in unhydrous methanol are added. The reaction solution is left to stand for 30 minutes at 0 and then for 3 hours at room temperature, whereupon it is evaporated to dryness in vacuo. The residue is recrystallized from ethanol whereupon N-(3,4-dichlorophenyl-carbamoyl)-D-glucosamine is obtained; M.P. 171- 172", [a] +32.4, c.=1 in dimethyl formamide.

(c) 9.5 parts of the product obtained according to (b) and 1 00 parts by volume of 20% acetic acid are heated for 30 minutes in a boiling water bath and the mixture is filtered, While still hot, with charcoal. The filtrate is left to crystallize, the 2-oxo-3-(3',4'-dichlorophenyl)-4,5- D-glucopyrano-tetrahydro-imidazole obtained is filtered off and recrystallized from alcohol, M.P. 206-207", [a] +'148.7, c.=1.02 in dimethyl formamide.

EXAMPLE 2 (a) 15 parts of ,B-l,3,4,6-tetra-acetyl-D-pyranoglucosarnine in 250 parts by volume of anhydrous benzene and lize.

7.8 parts of 3,4-dimethyl phenyl mustard oil are boiled under reflux for 2 hours while excluding moisture. Petroleum ether is then carefully added to the reaction solution until it is just about to become cloudy whereupon the product is left to crystallize. Recrystallized from ethanol, the ,8-1,3,4,6-tetra-acetyl-N-(3,4-dimethylphenylthiocarbamoyl)-D-pyranoglucosan1ine melts at 157-l58, [a] +44.9, c.=1 in dimethyl formamide.

(b) 12 parts of the produce obtained according to (a) are dissolved in parts by volume of anhydrous methanol and, at 0, 400 parts by volume of a solution, saturated at 0, of ammonia in anhydrous methanol are added. The reaction solution is left for 2 hours at 0 and then for 4 hours at room temperature and afterwards evaporated to drynuess in vacuo. The residue is dissolved as far as possible with 30 parts of hot water and, after filtering, the aqueous solution is left to crystal- The N-(3,4-dimethylphenylthiocarbamoyl) D-glucosamine melts at 188l90, [a] +6.3 c.=1 in dimethyl formamide.

(c) 2 parts of the product obtained according to (b) and 15 parts by volume of 20% acetic acid are heated for 30 minutes in a boiling Water bath. After cooling, the precipitate is filtered oil and recrystallized from Water.

25 The 2-thiono-3-(3,4-dimethylphenyl) -4,5-D-glucopyra- Table I GHQ-DAG R1 H EBIGX-NH R:

R1 }T Explf x M.P., When erystal- T(C.) n 01in No. degrees lize-dfrom- DMF 3, (degrees) B 01 3a Q-or s 134-135 Ether a4 +1119 1.05

411 --o1 0 209-210 Ethanol 24 +ss.1 1.02

52. @431 s -161 Methanol 23 +2115 1 e11 --Noi 0 220-222 Ethanol 24 +1011 0.98

7a orn 0 220-201 do 24 +3110 1.03

as 0H= s 158-159 Methanol 24 +s5.e 1.01

911 -oom 0 203-204 Ethanol 25 +3112 1.01

10b --oom s 139-141 .....(10 24 +331 1198 See footnote at end of table.

Table IlContinued Q [1 Exp]. X M.P., When crystal- T( o. '1) 0.111

No. degrees hzedfrom- DMF R2 (degrees) 120...... -c11= 0 184-186 Ethanol +410 1.1

01 13b- Q 0 101-104 do 25 +412 1.00

14b s 192-194 Ethannllwatern 27 -13.5 1.01

111 ethanol. 1 DMF/HQO on.

Table III Compounds of Formula. I:

CHPOH ---0 E1 HO OH H NQ V I l R:

ZEN-- x R;

[ Expl. x 111.1 Whencrystal- T(O.) D 0.111 No. degrees lized irom' DMF R2 (degrees) R3 01 3c Q01 185-186 Water 24 +721 1.00

40 @411 0 221-222 Ethanol 24 +1410 1.01

@431 232-233 Ethanol/water 24 +301 1 00 Q-Nm 0 233-234 Water 24 +2312 1- @4311 237-233 Water 24 +105 0.88

--OCH1 0 201-202 do 24 +1111 1 Q-OOH; 235-236 Ethanol/water" 24 +79.6 1

Q 0 200-201 Ethanol 24 +311 1.01

12c Q 215-216 Water I 25 +1101 1 Table III-Continued 6! Exp]. X M.P., When crystal- T C.) D 0.111

No. degrees lized from- DMF R2 (degrees) 3 CH3 13c Q-cm 0 166-167 -do 25 -l-l24.6 1

C1 14c Q 0 107-108 d0 25 +l46.2 1.04

G1 I 150 Q s 191-192 do 25 +66.2 1

What I claim is: sisting of hydrogen, halogen, lower alkyl and lower 1. A compound of the formula 25 alkoxy, and

CHFOH X represents a member selected from the group con- I 0 sisting of oxygen and sulfur. H 2. 2-oXo-3:(3',4'-dichlorophenyl) 4,5-D-glucopyrano- R1 tetrahydrolmldazole.

HO OH H 30 3. 2-thiono-3:(? ',4-dichlorophenyl)-4,5 D glucopy- I I I R rano-tetrahyd-rolmldazole. H HN OX I 4. 2-thi0no-3-(3',4'-dimethylphenyl) 4,5 D-glucopyin which rano-tetrahydroimidazole.

R1 f P f h l i ig l l the li 35 References Cited in the file of this patent slstmg o aogen, ower a y, ower a oxy, tnfiuoromethyl and Him UNITED STATES PATENTS R represents a member selected from the group con- 2,891,944 Boettner June 23, 1959 

1. A COMPOUND OF THE FORMULA 